Pazopanib Hydrochloride and Bevacizumab in Treating Patients With Previously Untreated Metastatic Kidney Cancer

Sponsor
Roswell Park Cancer Institute (Other)
Overall Status
Recruiting
CT.gov ID
NCT01684397
Collaborator
GlaxoSmithKline (Industry)
51
5
1
120
10.2
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Study Details

Study Description

Brief Summary

This phase I/II trial studies the side effects and best dose of pazopanib hydrochloride and bevacizumab and to see how well they work in treating patients with previously untreated kidney cancer that has spread to other places in the body (metastatic). Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Pazopanib hydrochloride may also stop the growth of tumor cells by blocking blood flow to the tumor. Monoclonal antibodies, such as bevacizumab, can prevent tumor growth by blocking the ability of tumor cells to grow and spread. Giving pazopanib hydrochloride together with bevacizumab may kill more tumor cells.

Condition or Disease Intervention/Treatment Phase
  • Biological: Bevacizumab
  • Other: Laboratory Biomarker Analysis
  • Drug: Pazopanib Hydrochloride
  • Other: Pharmacological Study
Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:
    1. To determine the safe phase II dose of this novel regimen. (Phase I)
    1. To determine the median progression free survival (PFS) from this novel regimen. (Phase II)
SECONDARY OBJECTIVES:
  1. To evaluate the safety and toxicity of the proposed regimen. (Phase I) II. To evaluate the response rate. (Phase I) III. To evaluate the pharmacokinetics of pazopanib (pazopanib hydrochloride). (Phase I) IV. To evaluate the vascular endothelial growth factor (VEGF) levels and myeloid derived suppressor cell (MDSC) levels at various time points and correlate with response. (Phase I) V. To evaluate the safety and toxicity of this new regimen. (Phase
    1. To evaluate the VEGF levels, interleukin (IL)-8 levels and MDSC levels at various time points and correlate with outcome. (Phase II) VII. To evaluate the PFS rate at 12 months. (Phase II) VIII. To evaluate overall survival. (Phase II)

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive pazopanib hydrochloride orally (PO) on days 1-28, and bevacizumab intravenously (IV) over 30-90 minutes on days 36 and 50. Courses repeat every 70 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and Phase II patients are followed up by telephone every 12 months

Study Design

Study Type:
Interventional
Anticipated Enrollment :
51 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I/II Trial of Pazopanib Alternating With Bevacizumab in Treatment-Naive Metastatic Clear Cell Renal Cell Carcinoma Patients
Actual Study Start Date :
Nov 21, 2012
Anticipated Primary Completion Date :
Nov 21, 2022
Anticipated Study Completion Date :
Nov 21, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (pazopanib hydrochloride and bevacizumab)

Patients receive pazopanib hydrochloride PO on days 1-28 and bevacizumab IV over 30-90 minutes on days 36 and 50. Courses repeat every 70 days in the absence of disease progression or unacceptable toxicity.

Biological: Bevacizumab
Given IV
Other Names:
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
  • Recombinant Humanized Anti-VEGF Monoclonal Antibody
  • rhuMab-VEGF
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Drug: Pazopanib Hydrochloride
    Given PO
    Other Names:
  • GW786034B
  • Votrient
  • Other: Pharmacological Study
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. Median PFS (Phase II) [Up to 30 days post-treatment]

      Distributions of continuous variables will be summarized with commonly used statistics (mean, standard deviation, median, etc.), with sub-group associations tested using the Wilcoxon Rank Sum test.

    2. Optimal phase II dose, defined as the largest dose level at which less than 2 out of the 6 patients experienced dose-limiting toxicity, graded according to Common Terminology Criteria for Adverse Events version 4.0 (Phase I) [Up to 140 days]

      The frequency of toxicities will be tabulated for the dose estimated to be the maximum-tolerated dose.

    Secondary Outcome Measures

    1. Incidence of grade 3 or higher toxicities, graded according to CTCAE version 4.0 [Up to 30 days post-treatment]

      Categorical variables will be summarized in contingency tables, with associations of interest assessed using Fisher's exact test. The frequency of toxicities will be tabulated by grade across all dose levels and courses.

    2. Overall survival (Phase II) [From the date of study enrollment to the date of death from any cause, assessed up to 30 days post-treatment]

      Will be obtained using Kaplan-Meier and Proportional Hazards methods.

    3. PFS rate at 12 months (Phase II) [At 12 months]

      Distributions of continuous variables will be summarized with commonly used statistics (mean, standard deviation, median, etc.), with sub-group associations tested using the Wilcoxon Rank Sum test.

    4. Response rate according to RECIST 1.1 (Phase I) [Up to 30 days post-treatment]

    Other Outcome Measures

    1. IL-8 levels [Up to 30 days post-treatment]

      Distributions of continuous variables will be summarized with commonly used statistics (mean, standard deviation, median, etc.), with sub-group associations tested using the Wilcoxon Rank Sum test.

    2. MDSC levels [Up to 30 days post-treatment]

      Distributions of continuous variables will be summarized with commonly used statistics (mean, standard deviation, median, etc.), with sub-group associations tested using the Wilcoxon Rank Sum test.

    3. Pazopanib exposure as measured by pharmacokinetics parameters [Course 1 on day 1 at pre-dose, 2 hours, and 4 hours post-dose; day 15 at pre-dose and 2 hours post-dose; and day 29]

    4. VEGF levels [Up to 30 days post-treatment]

      Distributions of continuous variables will be summarized with commonly used statistics (mean, standard deviation, median, etc.), with sub-group associations tested using the Wilcoxon Rank Sum test.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Biopsy/pathology-proven clear cell renal cell carcinoma (CCRCC) with metastases

    • Have an Eastern Cooperative Oncology Group (ECOG) performance status =< 1

    • Hemoglobin >= 10 gm/dL

    • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

    • Platelets >= 100 x 10^9/L

    • Total bilirubin =< upper limit of normal (ULN)

    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< ULN

    • International normalization ratio (INR) and activated partial thromboplastin time (aPTT) < 1.2 x ULN

    • Serum creatinine < 1.5 mg/dL or if serum creatinine > 1.5 mg/dL then calculate creatinine clearance (CrCL) > 30 mL/min

    • Urine protein to creatinine ratio =< 1 (if urine protein creatinine ratio is > 1, then a 24-hour urine total protein must be assessed; subjects will be ineligible if the 24-hour urine protein is found to be > 1 gm)

    • Normal cardiac ejection fraction (> 50%) by multi gated acquisition scan (MUGA) or echocardiogram

    • Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria present

    • Ability to swallow and retain oral medication

    • Subjects of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

    • Subject or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

    Exclusion Criteria:
    • Subjects with known brain metastases should be excluded from this clinical trial

    • Prior VEGF targeted therapies for renal cell carcinoma (RCC) including adjuvant or neoadjuvant treatments; in phase 1 only, one prior therapy with high dose IL-2 or anti-programmed cell death (PD)-1 compound alone or in combination with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) targeting drug is allowed on the trial

    • Subjects diagnosed with another cancer in the past 3 years; excluding basal cell carcinoma or squamous cell carcinoma, of skin which were completely cured by resection

    • Concurrent use of another anti-cancer drug including an investigational anti-cancer agent

    • Major surgery within 28 days prior to treatment or major surgery planned during the next 6 months

    • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic or psychiatric illness/social situations that would limit compliance with study requirements

    • History of any of the following cardio-vascular condition:

    • Myocardial infarction (MI)

    • Unstable angina

    • Coronary artery bypass grafting (CABG)-unless patient had a negative stress test within 6 months of screening

    • Coronary angioplasty or stenting

    • Symptomatic peripheral arterial disease (PAD)

    • History of symptomatic chronic congestive heart failure (CHF)

    • History of cerebrovascular accidents including transient ischemic attacks (TIA)

    • Corrected QT interval (QTc) > 480 msec

    • Uncontrolled hypertension (systolic blood pressure [BP] > 150 mm Hg or diastolic BP of > 90 mm Hg); if the screening BP is elevated, adjustments in anti-hypertensives are permitted and a re-screening will be permitted for BP assessment with three consecutive values obtained 2 minutes apart; the 3 values have to be below 150/90 mm Hg for eligibility and can only be obtained after 2 days of the last change in anti-hypertensive medication; use of clonidine is not permissible for adjusting the BP during this period

    • History of deep vein thrombosis (DVT) or pulmonary embolism (PE) in the past 6 months

    • Subjects should not have packed red blood cells (PRBC) or platelet transfusion within 14 days of the screening

    • Evidence of active bleeding or bleeding disorder

    • Subjects currently on anti-coagulation therapy are not eligible

    • Unable to discontinue the use of prohibited medications

    • Pregnant or nursing female subjects

    • Unwilling or unable to follow protocol requirements

    • Any condition which in the investigator's opinion deems the subject an unsuitable candidate to receive study drug

    • Received an investigational agent within 30 days prior to enrollment

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 The University of Kansas Cancer Center Westwood Kansas United States 66205
    2 Karamanos Cancer Institute Detroit Michigan United States 482018
    3 Roswell Park Cancer Institute Buffalo New York United States 14263
    4 University of Pittsburgh Cancer Institute (UPCI) Pittsburgh Pennsylvania United States 15232
    5 Medical College of Wisconsin Milwaukee Wisconsin United States 53226

    Sponsors and Collaborators

    • Roswell Park Cancer Institute
    • GlaxoSmithKline

    Investigators

    • Principal Investigator: Saby George, Roswell Park Cancer Institute

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Roswell Park Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT01684397
    Other Study ID Numbers:
    • I 191711
    • NCI-2012-01247
    • 13-069
    • I 191711
    First Posted:
    Sep 13, 2012
    Last Update Posted:
    May 9, 2022
    Last Verified:
    May 1, 2022

    Study Results

    No Results Posted as of May 9, 2022